In the production of pharmaceuticals, the technique of multichamber chamber cartridges for separately storing pharmaceuticals and a liquid diluent, just prior to the administration, has found a wide spread use for such pharmaceutically active components which are unstable during storage as a solution. Dual chamber cartridges has become state of the art especially for providing suitable administration systems for lyophilized polypeptides or proteins produced by recombinant technology, such as human growth hormone and Factor VIII which must be stored in solid form to not lose activity. Normally, a solution of the pharmaceutical is introduced and freeze dried to solid form directly in a designated chamber of a cartridge, or of a syringe barrel, which thereafter is sealed until just prior to the administration, as is disclosed in the European patent specification EP 331 152. The two chambers containing a solid pharmaceutical and a liquid diluent for reconstitution are often separated by a movable wall in the form of a flexible piston which seals against the interior wall of the glass cartridge. The rear chamber, usually containing the liquid, is also sealed at its rear end with a rear piston which seals against the interior wall. When the cartridge shall be used, the rear piston is pushed forward, whereupon a pressure is exerted on the liquid diluent large enough to urge the movable wall a determined distance forwards to a non-sealing position in front of a bypass channel where the liquid can flow from the rear chamber to the front chamber and dissolve the solid pharmaceutical to provide a reconstituted preparation possible to administer immediately.
In many applications it is important that the reconstitution is performed very carefully, because the proteins are highly sensitive for shaking and whirling which lead to loss of biological activity. A solution to this problem is introduced in the European patent specification EP 298 067 which describes how to successfully perform a gentle reconstitution in a dual-chamber cartridge operated by an injection device. It is disclosed how a screw motion can enable a piston rod to perform a controlled forwards motion while displacing the rear piston of the cartridge forwards to a bypass position, so a controlled liquid overflow to the front chamber gives a controlled and mild reconstitution.
However, conventional dual-chamber cartridges of the type described with a external, radially extended bypass channel formed as a longitudinal ridge are bulky and makes it necessary to use injection devices with undesirably thick barrels. This is a drawback when there is a demand to reduce injection devices both in longitudinal and radial size, as is disclosed in the International patent application WO 93/20869. In addition, such bulky bypasses makes the cartridges sensitive during the handling and leads to that many expensive products must be discarded. Moreover, such bypass channels in the form of longitudinal ridges are usually made by blow forming heated glass tubes with pressurized air, which is an expensive method with a rather low precision and reproducibility.
According to the International patent application WO 93/20868, the bypasses formed of a longitudinally extended ridge can be successfully substituted with a bypass area consisting of controlled modifications in the interior wall of a glass cartridge. Such a modified bypass area can typically comprise a plurality of shallow channels distributed around the interior periphery of the cartridge. A highly advantageous embodiment of this type of bypass area is disclosed in the International patent application WO 95/11051. Such a modified area has a plurality of lands and grooves with an inclined direction in relation to the axial direction of the cartridge, and is axially extended to form a predetermined bypass zone in the interior peripheral wall. Preferably, the lands and grooves extend inward from the interior wall of the cartridge, so the interior diameter between the lands is smaller than the nominal diameter of the cartridge. It was also shown that when manufacturing the bypass area with a rotating embossing tool on the heated glass cartridges, vibrations due to the embossing action could appear which might lead to a distortion of the cartridge. This problem has found its solution unexpectedly well by letting the lands and grooves be embossed at an angle to the longitudinal axis of the cartridge. It was found that if the angle were between 5 and 45 degrees, preferably between 10 and 30 degrees and most preferably about 20 degrees, no such vibrations occurred.
The present invention provides a novel method of manufacturing such lands and grooves by treating glass cartridges or comparable hollow glass articles of a tubular form with a multistep method of plastically forming a zone of their interior surface, which is found to be surprisingly advantageous when a relative rolling off motion is provided between an embossing mandrel and the cartridge during the forming.
The present invention is also directed to glass cartridges having a bypass zone manufactured by said method.
In addition, the present invention provides a specific embossing mandrel which is to be used in the said method.